Abstract Cardiovascular complications of diabetes continue to remain a huge burden on the health care system. Of all the currently approved anti-diabetic therapies, only one class to date has demonstrated any significant improvement in cardiovascular outcomes. Novel therapeutic strategies that can couple improvements in glycemic control with reduction of cardiovascular complications would represent a significant advancement in how we manage these challenging patient population. To this end, we propose to investigate an exciting novel strategy to target the endothelial based signaling cascade driven by the G protein coupled receptor APLNR, as we characterize the mechanistic basis of its anti-glycemic and atheroprotective effects. A key mechanistic basis for this strategy, as outlined in this proposal, is to exploit its function as the metabolic transport barrier that actively regulates the transport and uptake of fatty acid in target organs such as skeletal muscles, which in turn determines insulin sensitivity and glucose utilization. Our exciting preliminary data, including: : 1) demonstration of marked impairment of glycemic control in conditional, endothelial specific Aplnr deleted mice, 2) discovery of FOXO1, a key metabolic transcription factor, as a novel signaling target of apelin, whereby apelin induces its inactivation via phosphorylation and cytoplasmic translocation, 3) demonstration that the negative regulation of FOXO1 by apelin in the endothelium leads to suppression of FABP4 (AP2) expression, which regulates trans- endothelial FA transport, and 4) identification of novel endothelial based crosstalk between apelin/APLNR and insulin/insulin receptor (IR) signaling. Based on these provocative preliminary data, we will address the hypothesis that endothelial APLNR signaling is an essential regulator of the endothelial function as a gatekeeper of FA uptake and transport. Aim 1 will utilize in vivo and in vitro approaches to determine the mechanism of crosstalk between apelin-APLNR signaling and insulin-IR signaling. Aim 2 will determine the metabolic role of elabela, the recently identified second APLNR ligand. Aim 3 will push forward the translational application of these findings by testing the efficacy and mechanistic basis of novel APLNR agonists in experimental diabetes and atherosclerosis models. Overall, our studies will significantly expand our knowledge of a novel endothelial- based signaling paradigm that regulates energy resource utilization, with multiple implications in the context of the worldwide epidemic of diabetes and its associated cardiovascular complications.